The present invention relates to novel N-alkoxyalkyl-N,N-dialkylamine derivatives or salts thereof.
Dementia is classified into cerebrovascular dementia and neurodegenerative dementia, and a variety of agents such as ameliorants of cerebral circulation, ameliorants of cerebral function, etc. are used for treating these diseases.
The 1,2-ethanediol derivatives or salts thereof described in JP-A-3-232830 and JP-A-4-95070 are useful as the ameliorants of cerebral function, among which especially preferable is (R)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethanol hydrochloride (hereinafter referred to as T-588).
Among the neurodegenerative dementia, the most popular is Alzheimer""s disease (hereinafter referred to as AD), which is characterized by appearance of senile plaque of which the main component is an amyloid xcex2 protein (hereinafter referred to as Axcex2) derived from a xcex2 amyloid precursor protein [Biochemical and Biophysical Research Communications, Vol. 120, Page 885 (1984)].
Axcex2 is considered to deposit on the nerve cells or blood vessels and to cause a symptom of dementia, etc. [Annual Review of Cell Biology, Vol. 10, Page 373 (1994)].
Further, it has also been reported that Axcex2 itself causes the apoptosis of cultured nerve cells (shrinkage of cell volume, a cell death, via the expression of gene, characterized by fragmentation of DNA) [Brain Research, Vol. 661, Page 147 (1994); Molecular Neurobiology, Vol. 10, Page 19 (1995)].
On the other hand, a rise in the quantity of 4-hydroxy-2-nonenal (hereinafter referred to as HNE) in the brain of AD patients has been reported [American Journal of Pathology, Vol. 150, Page 437 (1997)], and it has also been reported that HNE takes part in the cell death of cultured nerve cells caused by Axcex2 through intermediation of peroxidation of lipids [The Journal of Neuroscience, Vol. 17, Page 1046 (1997)].
It has also been reported that a cell death is caused if HNE is applied to upon cultured nerve cells, and that this cell death is apoptosis [The Journal of Neuroscience, Vol. 17, Page 5089 (1997)].
Further, a possibility that HNE is produced by an oxidation stress in various neurodegenerative diseases and the HNE exerts damage to nerve cells in the brain and spinal cord. For example, a rise in the quantity of HNE has been reported in the brain of patients of the Parkinson""s disease [Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, Page 2696 (1996)], and in the spinal cord of patients of the amyotrophic lateral sclerosis [Annals of Neurology, Vol. 44, Page 696 (1998)].
For these reasons, agents for controlling the neurocytotoxicity caused by Axcex2 and HNE are being studied for treating the neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis, etc.
Now, it is well known that neurotrophic factors such as a nerve growth factor (NGF) affecting the growth and regeneration of nerves exist in living organisms.
The neurotrophic factors are reported to interact not only to the central nervous diseases such as Alzheimer""s disease but also to the peripheral nervous diseases such as diabetic neuropathy, drug-induced neuropathy, etc., and attempts are being made to use the neurotrophic factors for treatment of these diseases [Nou to Shinkei, Vol. 43, No. 12, Page 1101 (1991)].
Further, it has been reported that the impairment in the neuronal conduction in model animals with crushed sciatic nerve can be ameliorated by the regeneration of nerves promoted by NGF [Microsurgery, Vol. 16, Page 547 (1995)]. However, since neurotrophic factor is a protein of high molecular weight, there are many unsolved technical problems to apply it to nervous diseases.
Thus, it is demanded to develop a low molecular weight compound which is the same in function as the neurotrophic factor.
T-588 which is useful as a cerebral function ameliorant exhibits a protective action on the nerve cell death caused by Axcex2 [Society for Neuroscience, Abstracts, Vol. 24, No. 1, Page 228 (1998)], and further has an activity of reinforcing the function of NGF (WO96/12717), and is useful as an agent for treating the diseases of the central and peripheral nervous systems. However, a low molecular compound having yet stronger nerve cell-protecting and nerve regeneration-promoting activities with an intense anti-hypoxic activity is awaited.
The present inventors have conducted extensive studies with the aim of solving the problem mentioned above. As a result, it has been found that N-alkoxyalkyl-N,N-dialkylamine derivatives represented by the following general formula [1]: 
wherein R1 and R2 are the same or different and represent at least one group selected from the group consisting of a hydrogen atom, a halogen atom, an unsubstituted or substituted alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic group, an unprotected or protected amino, hydroxyl or carboxyl group, a nitro group and an oxo group; R3 and R4 are the same or different and represent an unsubstituted or substituted alkyl, cycloalkyl or aralkyl group; each of mR5xe2x80x2s, mR6xe2x80x2s, nR7xe2x80x2s and nR8xe2x80x2s are the same or different and represent a hydrogen atom or an alkyl group; the ring D represents a 5- or 6-membered heterocyclic or hydrocarbon ring; m represents an integer of 1-5; and n represents an integer of 1-6,
or its salt have an anti-hypoxic activity, a nerve-protecting activity and a nerve regeneration promoting activity and are useful as an agent for treating neurodegenerative diseases. Based on this finding, the present invention has been accomplished.
Hereunder, the present invention will be explained in detail.
As used in this specification, the terms have the following meanings, unless otherwise indicated. The term xe2x80x9chalogen atomxe2x80x9d means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; xe2x80x9calkyl groupxe2x80x9d means a straight or branched chain C1-12 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; xe2x80x9clower alkyl groupxe2x80x9d means a straight or branched chain C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like; xe2x80x9ccycloalkyl groupxe2x80x9d means a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; xe2x80x9caryl groupxe2x80x9d means a phenyl, naphthyl, indanyl or indenyl group; xe2x80x9caralkyl groupxe2x80x9d means an ar-C1-6-alkyl group such as benzyl, diphenylmethyl, trityl, or phenethyl group; xe2x80x9calkoxy groupxe2x80x9d means a straight or branched chain C1-12 alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like; xe2x80x9clower alkoxy groupxe2x80x9d means a straight or branched chain C1-6 alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like; xe2x80x9caryloxy groupxe2x80x9d means a phenyloxy, naphthyloxy, indanyloxy or indenyloxy group; xe2x80x9calkylthio groupxe2x80x9d means a C1-12 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio and the like; xe2x80x9clower alkylthio groupxe2x80x9d means a C1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio and the like; xe2x80x9carylthio groupxe2x80x9d means a phenylthio, naphthylthio, indanylthio or indenylthio group and the like; xe2x80x9calkenyl groupxe2x80x9d means a C2-12 alkenyl group such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and the like; xe2x80x9clower alkenyl groupxe2x80x9d means a C2-6 alkenyl group such as vinyl, propenyl, butenyl, pentenyl, hexenyl and the like; xe2x80x9calkenyloxy groupxe2x80x9d means a C2-12 alkenyloxy group such as vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy and the like; xe2x80x9clower alkenyloxy groupxe2x80x9d means a C2-6 alkenyloxy group such as vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy and the like; xe2x80x9calkynyl groupxe2x80x9d means a C2-6 alkynyl group such as ethynyl, 2-propynyl, 2-butynyl and the like; xe2x80x9cacyl groupxe2x80x9d means formyl, alkylcarbonyl or aroyl group; xe2x80x9calkylcarbonyl groupxe2x80x9d means a C2-6 alkylcarbonyl group such as acetyl, propionyl and the like; xe2x80x9caroyl groupxe2x80x9d means an arylcarbonyl group such as benzoyl, naphthylcarbonyl and the like; xe2x80x9cacyloxy groupxe2x80x9d means an acyloxy group such as acetyloxy, pivaloyloxy, phenylacetyloxy, 2-amino-3-methylbutanoyloxy, ethoxycarbonyloxy, benzoyloxy, 3-pyridylcarbonyloxy and the like; xe2x80x9calkylamino groupxe2x80x9d means a mono- or di-C1-6-alkylamino group such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, diisopropylamino, di-n-butylamino and the like; xe2x80x9calkylsulfonyl groupxe2x80x9d means a C1-12 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl and the like; xe2x80x9clower alkylsulfonyl groupxe2x80x9d means a C1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl and the like; xe2x80x9carylsulfonyl groupxe2x80x9d means phenylsulfonyl group, p-toluenesulfonyl group, naphthylsulfonyl group or the like; xe2x80x9calkylsulfonyloxy groupxe2x80x9d means a C1-12 alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, hexylsulfonyloxy, heptylsulfonyloxy, he ptylsulfonyloxy, octylsulfonyloxy and the like; xe2x80x9clower alkylsulfonyloxy groupxe2x80x9d means a C1-6 alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy and the like; xe2x80x9carylsulfonyloxy groupxe2x80x9d means phenylsulfonyloxy, p-toluenesulfonyloxy, naphthylsulfonyloxy or the like; and xe2x80x9cheterocyclic groupxe2x80x9d means a 5- or 6-membered, fused ring type or crosslinked ring heterocyclic group containing at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms which ring may contain one or more oxygen atoms or sulfur atoms as hetero atoms constituting the ring, such as pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolizinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3-a]pyridyl, benzo[b]piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl, isoquinolyl, 1,3-benzodioxonyl, 1,4-benzodioxanyl and the like.
The 5- or 6-membered heterocyclic ring represented by D includes heterocyclic rings containing at least one hetero atom selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom as the hetero atom constituting the ring, of which examples include 5- or 6-membered aromatic heterocyclic rings such as triazine, pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyran and furazan rings and the like and 5- or 6-membered aliphatic heterocyclic rings such as tetrahydro-2H-pyran, tetrahydro-2H-thiopyran, piperidine, dioxane, oxathiane, morpholine, thiomorpholine, dithiane, piperazine, pyrrolidine, tetrahydrothiophene, tetrahydrofuran, pyrazolidine, imidazolidine, tetrahydroisothiazole, 1,3-dioxalane, 1,3-thiazolane, tetrahydroisoxazole, 1,3-oxazolane, dithiolane, oxathiolane and dioxalane rings and the like.
The 5- or 6-membered hydrocarbon ring represented by D includes 5- or 6-membered unsaturated hydrocarbon rings such as benzene, cyclohexene and cyclopentene rings and the like and saturated hydrocarbon rings such as cyclohexane and cyclopentane rings.
The substituent on the alkyl, cycloalkyl and aralkyl groups represented by R3 and R4 and the alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, alkylsulfonyl, arylsulfonyl, carbamoyl and heterocyclic groups represented by R1 and R2 includes at least one group selected from the group consisting of halogen atom, nitro group, lower alkyl group, cycloalkyl group, aryl group, aralkyl group, lower alkoxy group, aryloxy group, lower alkylthio group, lower alkenyl group, alkynyl group, alkylsulfonyl group, arylsulfonyl group, acyl group, acyloxy group, alkylamino group, carbamoyl group, unprotected or protected amino group, unprotected or protected hydroxyl group, unprotected or protected carboxyl group, heterocyclic group and the like.
The protecting group for carboxyl group includes all the groups usually usable for protection of carboxyl group, of which the examples include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, butyl, tert-butyl and the like; aryl groups such as phenyl, naphthyl and the like; ar-(lower alkyl) groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl and the like; acyl-(lower alkyl) groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; halogeno-(lower alkyl) groups such as 2,2,2-trichloroethyl and the like; lower alkylsilyl-lower alkyl groups such as 2-(trimethylsilyl)ethyl and the like; acyloxy-(lower alkyl) groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocycle-lower alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such as cyclohexyl and the like; lower alkoxy-lower alkyl groups such as methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl and the like; ar-(lower alkoxy)-(lower alkyl) groups such as benzyloxymethyl and the like; lower alkylthio-lower alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthio-lower alkyl groups such as phenylthiomethyl and the like; lower alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.
The protecting groups for hydroxyl group include all the groups usually usable for protection of hydroxyl group, of which the examples include acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)-ethoxy-carbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, ethoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl and the like; lower alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like; lower alkenyl groups such as allyl and the like; ar-(lower alkyl) groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; lower alkoxy- and lower alkylthio-lower alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxyethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl and the like; lower alkyl- and aryl-sulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.
The protecting groups for amino group include all the groups usually usable for protection of amino group, of which the examples include acyl groups such as trichloroethoxycarbonyl, tribromoethoxy-carbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like; ar-(lower alkyl) groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthio and the like; alkyl- or aryl-sulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; di-(lower alkylamino)-lower alkylidene groups such as N,N-dimethylamino-methylene and the like; ar-(lower alkylidene) groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene and the like; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene and the like; diaryl- or di-ar-(lower alkylphosphoryl) groups such as diphenylphosphoryl, dibenzylphosphoryl and the like; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl and the like; and substituted silyl groups such as trimethylsilyl and the like.
The salts of the compound of general formula [1] include usually known salts formed at the site of a basic group such as amino group and those formed at the site of an acidic group such as hydroxyl group, carboxyl group or the like. Examples of the salt formed at the site of a basic group include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, salts of organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, trifluoroacetic acid and the like, and salts of sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. Examples of the salt formed at the site of an acidic group include salts of alkali metals such as sodium, potassium and the like; salts of alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts of nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-xcex2-phenethylamine, 1-ephenamine, N,Nxe2x80x2-dibenzylethylenediamine and the like. Among the salts mentioned above, preferred are pharmacologically acceptable ones.
Next, typical examples of the compound of the present invention are listed in the following Tables 1 to 7.
In the tables, Me means methyl group, Et means ethyl group, and Ph means phenyl group.
Next, the process for producing the N-alkoxyalkyl-N,N-dialkylamine derivatives of general formula [1] or salts thereof will be described below.
The N-alkoxyalkyl-N,N-dialkylamine derivatives of the general formula [1] or salts thereof can be produced according to the processes known per se or appropriate combination of such processes, such as the processes shown below.
Production Process 1
Production Process 2
Production Process 3
wherein R1, R2, R3, R4, m and n are as defined above and X1 and X2 independently represent a removing group.
As said removing group, for example, halogen atom, lower alkylsulfonyloxy group, arylsulfonyloxy group and the like can be referred to.
Next, the steps constituting the processes will be explained.
Production Process 1
A compound of general formula [2a] is reacted with a compound of general formula [3a] in the presence of a base to form a compound of general formula [1a].
This reaction is carried out according to a method well known per se, such as the method described in Tetrahedron, Letters, Vol. 38, Pages 3251-3254 (1975) or Shin Jikken Kagaku Koza, Vol. 14, [I], edited by Chemical Society of Japan, Pages 567-611 (1977, published by Maruzen) or any method analogous thereto.
As the base, for example, sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert-butoxide and the like can be used.
The solvents which can be used in this reaction include, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; tertiary alcohols such as tert-butanol and the like; water; etc. These solvents can be used in the form of a mixture, if desired.
This reaction can be carried out in the presence or absence of a catalyst.
As the catalyst, the generally known quaternary ammonium phase transfer catalysts are used, among which preferred are tetra-n-butylammonium hydrogen sulfate, tetra-n-butylammonium bromide, and the like.
The compound of general formula [3a] and the base are both used at least in an equimolar amount to the compound of general formula [2a], and preferably in an amount of 1-20 mol per mol of the compound [2a]. The catalyst is used in an amount of 0.01-0.30 mol per mol of the compound [2a].
This reaction is usually carried out at a temperature of xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably 0xc2x0 C. to +150xc2x0 C., for a period of 10 minutes to 20 hours.
Production Process 2
(1) A compound of general formula [4a] or a reactive derivative thereof is reacted with a compound of general formula [5], whereby a compound of general formula [6a] can be produced.
This reaction is carried out according to a method known per se, such as the method described in Jikken Kagaku Koza, Vol. 22, edited by Chemical Society Japan, Pages 137-173 (1922, Maruzen) or any method analogous thereto.
As the reactive derivative of the compound of general formula [4a], acid halides, acid anhydrides, activated amides, activated esters, and the like can be referred to, for example.
In a case where the compound [4a] is used in the form of a free acid, the reaction is preferably carried out in the presence of a condensing agent.
The condensing agents which can be used include, for example, N,N-dialkylcarbodiimides such as N,N-dicyclohexylcarbodiimide and the like; halogenating agents such as thionyl chloride and the like; halogenated alkyl esters such as ethyl chloroformate and the like; activating amidating agents such as carbonyl-diimidazole and the like; and azide-forming agents such as diphenylphosphoryl azide and the like, etc.
The condensing agent is used at least in an amount equimolar to the compound of general formula [4a], and preferably in an amount of 1-5 mol per mol of compound [4a].
The solvents which can be used in this reaction include, for example, water; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitrites such as acetonitrile and the like; hetero-aromatic compounds such as pyridine and the like; etc. These solvents can be used in the form of a mixture, if desired.
This reaction can be carried out in the presence of a base.
The bases which can be used include, for example, organic and inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride and the like.
The base is used in an amount of at lest equimolar amount to the compound of general formula [4a], and preferably 1-10 mol per mol of compound [4a].
The compound of general formula [5] is used in an amount of at least equimolar amount to the compound of formula [4a], and preferably 1-20 mol per mol of compound [4a].
This reaction is usually carried out at a temperature of xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably xe2x88x9230xc2x0 C. to +100xc2x0 C., for a period of 10 minutes to 20 hours.
(2) The compound of general formula [6a] is subjected to a conventional reduction reaction, whereby the compound of general formula [1a] can be obtained.
This reduction is carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15 [II], edited by Chemical Society of Japan, Pages 29-244 (1977, Maruzen), or any analogous method.
The solvents which can be used in this reaction include halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; alcohols such as methanol, ethanol, isopropanol and the like; etc. These solvents can be used in the form of a mixture, if desired.
As the reducing agent, for example, aluminum hydrides such as lithium aluminum hydride and the like; and borohydride such as diborane and sodium borohydride and the like can be used.
In a case where sodium borohydride is used as the reducing agent, the reaction is preferably carried out in the presence of a Lewis acid such as boron trifluoride diethyl etherate and the like.
The reducing agent is used in an amount of at least 0.5 mol and preferably in an amount of 1-10 mol, per mol of the compound [6a].
The Lewis acid is used at least in an equimolar amount to the reducing agent, and preferably in an amount of 1-20 mol per mol of the reducing agent.
This reaction is carried out at a temperature of usually xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably 0xc2x0 C. to +110xc2x0 C., for a period of 10 minutes to 20 hours.
Production Process 3
A compound of general formula [7a] is reacted with a compound of general formula [5] in the presence or absence of a base, whereby a compound of general formula [1a] can be obtained.
The solvents which can be used in this reaction include, for example, water; halogenated hydrocarbons such as methylene chloride, chloroform and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents can be used in the form of a mixture, if desired.
As the base which can be used as occasion demands, for example, organic and inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride and the like can be referred to.
The base is used at least in an equimolar amount to the compound of general formula [7a], and preferably in an amount of 1-20 mol per mol of the compound [7a].
If desired, this reaction can be carried out in the presence of a catalyst. The catalysts usable are, for example, potassium iodide, sodium iodide, and the like.
The catalyst is used in an amount of 0.01-10 mol and preferably 0.1-1 mol, per mol of the compound [7a].
The compound of general formula [5] at least in an equimolar amount to compound [7a], and preferably in an amount of 1-20 mol per mol of compound [7a].
This reaction is carried out at a temperature of usually 0xc2x0 C. to +200xc2x0 C. and preferably +20xc2x0 C. to +150xc2x0 C., for a period of 10 minutes to 20 hours.
It is also possible, if desired, to use the reagents and bases used in the above-mentioned Production Processes 1-3 as a solvent according to the nature thereof.
Production Process 4
Production Process 5
Production Process 6
Production Process 7
Production Process 8
Production Process 9
Production Process 10
wherein R1, R2, R3, R4, R5, R6, R7, R8, m and n are as defined above; R9 represents a hydrogen atom or an unsubstituted or substituted alkyl or cycloalkyl group; one of R10 and R11 represents a hydrogen atom or a substituent necessary for formation of a ring in the 5- or 6-membered heterocyclic ring or hydrocarbon ring; and X1, X2, X3 and X4 independently represent a removing group.
The substituent necessary for formation of a ring in the 5- or 6-membered heterocyclic or hydrocarbon ring includes, for example, halogen atom, an unsubstituted or substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkenyloxy, amino, alkylsulfonyl, arylsulfonyl, carbamoyl or acyl group, an unprotected or protected amino, hydroxyl or mercapto group, carboxyl group, and nitro group. As the removing group, for example, halogen atom, lower alkylsulfonyloxy group, arylsulfonyloxy group and the like can be referred to.
Next, the steps of the processes will be explained below.
Production Process 4
A compound of general formula [2] is reacted with a compound of general formula [3] in the presence of a base, whereby the compound of general formula [1] can be produced.
This reaction is carried out according to a method known per se, such as the same method as Production Process 1.
Production Process 5
(1) A compound of general formula [2] is reacted with a compound of general formula [39] in the presence of a base, whereby the compound of general formula [6] can be produced.
This reaction is carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [I], edited by Chemical Society of Japan, Pages 567-611 (1977, Maruzen), or any analogous method.
As the base, for example, organic or inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0 undec-7-ene, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydroxide, metallic sodium, lithium diisopropylamide, n-butyllithium, potassium tert-butoxide and the like can be referred to.
The solvents which can be used in this reaction include, for example, water; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; tertiary alcohols such as tert-butanol and the like; hetero-aromatic compounds such as pyridine and the like; etc. These solvents can be used in the form of a mixture, if desired.
Each of the compound of general formula [39] and the base is used at least in an equimolar amount to the compound of general formula [2], and preferably in an amount of 1-20 mol per mol of compound [2].
This reaction is carried out usually at xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably at 0xc2x0 C. to +150xc2x0 C., for a period of 10 minutes to 20 hours.
(2) A compound of general formula [6] is subjected to conventional reduction reaction, whereby the compound of general formula [1] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as Production Process 2 (2).
Production Process 6
(1) A compound of general formula [4] or a reactive derivative thereof is reacted with a compound of general formula [5], whereby a compound of general formula [6] can be obtained.
This reaction is carried out according to a method known per se, such as the same method as Production Process 2 (1).
(2) A compound of general formula [6] is subjected to conventional reduction reaction, whereby a compound of general formula [1] can be obtained.
This reaction is carried out according to a method known per se, such as the same method as Production Process 2 (2).
Production Process 7
A compound of general formula [7] is reacted with a compound of general formula [5] in the presence or absence of a base, whereby a compound of general formula [1] can be obtained.
This reaction is carried out according to a method well known in itself, such as the same method as Production Process 3.
Production Process 8
A compound of general formula [8] is reacted with a compound of general formula [9] in the presence or absence of a base, whereby a compound of general formula [1] can be obtained.
This reaction is carried out according to a method known per se, such as the same method as Production Process 3.
Production Process 9
(1) A compound of general formula [8] is reacted with a compound of general formula [10] or a reactive derivative thereof, whereby the compound of general formula [11] can be obtained.
This reaction is carried out according to a method known per se, such as the same method as Production Process 2 (1).
(2) A compound of general formula [11] is subjected to a conventional reduction reaction, whereby the compound of general formula [1] can be obtained.
This reaction is carried out according to a method known per se, such as the same method as Production process 2 (2).
Production Process 10
A compound of general formula [12] is subjected to a conventional ring-closing reaction, whereby the compound of general formula [1] can be obtained.
This reaction is carried out according to a method known per se, such as the method described in xe2x80x9cThe Chemistry of Heterocyclic Compoundsxe2x80x9d, Pages 16-80 (1988, Kodansha), Shin Jikken Kagaku Koza, Vol. 14, [II], edited by Chemical Society of Japan, Pages 788-796 (1977, Maruzen), and Shin Jikken Kagaku Koza, Vol. 14, [IV], edited by Chemical Society of Japan, Pages 1879-2406 (1977, Maruzen), or any analogous method.
Hereunder, the process is explained with reference to several specific examples.
(1) In cases where R10 is an amino group and R11 is an amino, hydroxyl or mercapto group, a compound of general formula [12] is reacted with a carboxylic acid or a compound equivalent to carboxylic acid, whereby a benzoazole derivative represented by general formula [1] can be obtained.
The solvents which can be used in this reaction include, for example, water; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; alcohols such as methanol, ethanol, isopropanol and the like; hetero-aromatic compounds such as pyridine and the like; etc. These solvents can be used in the form of a mixture, if desired.
As the carboxylic acid, formic acid, acetic acid, propionic acid, hydroxyacetic acid, phenylacetic acid and the like can be referred to.
The compound equivalent to carboxylic acid includes acid anhydrides such as acetic anhydride and the like; acid chlorides such as acetyl chloride, ethyl chloroacetate and the like; ortho esters such as ethyl orthoformate and the like; amidines such as acetoamidine and the like; and nitrites such as acetonitrile and the like.
The carboxylic acid or the compound equivalent to carboxylic acid are used at least in an equimolar amount to the compound of general formula [12], and preferably in an amount of 1-20 mol per mol of compound [12].
This reaction is usually carried out at a temperature of xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably at 0xc2x0 C. to +200xc2x0 C., for a period of 10 minutes to 20 hours.
(2) In case where both R10 and R11 are an amino group, compound [12] is reacted with an xcex1-carbonylcarbonyl derivative, whereby a quinoxalne derivative represented by general formula [1] can be obtained.
The solvents which can be used in this reaction include, for example, water; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; alcohols such as methanol, ethanol, isopropanol and the like; hetero-aromatic compounds such as pyridine and the like; etc. These solvents can be used in the form of a mixture, if desired.
As the xcex1-carbonylcarbonyl derivative, glyoxal, ethyl glyoxalate, pyruvic aldehyde, 1-phenyl-1,2-propanedione and the like can be referred to.
The xcex1-carbonylcarbonyl derivative is used at least in an equimolar amount to the compound of general formula [12], and preferably in an amount of 1-20 mol per mol of compound [12].
This reaction is usually carried out at xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably at 0xc2x0 C. to +200xc2x0 C., for a period of 10 minutes to 20 hours.
(3) In case where R10 is an alkylcarbonyl group and R11 is a hydroxyl or mercapto group, a compound of general formula [12] is reacted with an ester or a reactive carboxylic acid derivative in the presence of a base, whereby a chromone or thiochromone derivative represented by general formula [1] can be obtained.
The solvents which can be used in this reaction include, for example, ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like; alcohols such as methanol, ethanol, isopropanol and the like; and hetero-aromatic compounds such as pyridine and the like; etc. These solvents can be used in the form of a mixture, if desired.
As the ester, ethyl formate, methyl formate, ethyl acetate, ethyl benzoate and the like can be referred to.
As the reactive carboxylic acid derivative, acid anhydrides such as acetic anhydride and the like, acid chlorides such as acetyl chloride and the like, ortho esters such as ethyl orthoformate and the like, acetals such as N,N-dimethylformamide dimethyl acetals and the like, etc. can be referred to.
Each of the ester, the reactive carboxylic acid derivative and the base is used at least in an equimolar amount to the compound of general formula [12], and preferably in an amount of 1-20 mol per mol of compound [12].
This reaction is usually carried out at a temperature of xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably at 0xc2x0 C. to +130xc2x0 C., for a period of 10 minutes to 20 hours.
(4) In case where R10 is an alkyl group of which the xcex2 and xcex3 positions are substituted with carboxyl group, a compound of general formula [12] is subjected to a ring-forming reaction in the presence of an acid, whereby a 5- or 6-membered hydrocarbon ring derivative represented by general formula [1] can be obtained.
The solvents which can be used in this reaction include, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform and the like; etc. These solvents can be used in the form of a mixture, if desired.
The acids which can be used include mineral acids such as phosphoric acid, polyphosphoric acid, sulfuric acid, hydrofluoric acid and the like; Lewis acids such as phosphorus pentachloride, aluminum chloride, zinc chloride, tin chloride and the like; etc.
The acid is used at least in an equimolar amount to the compound of general formula [12], and preferably in an amount of 1-20 mol per mol of compound [12].
This reaction is usually carried out at a temperature of xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably at 0xc2x0 C. to +130xc2x0 C., for a period of 10 minutes to 20 hours.
If desired, it is also possible to use the reagents used in the above-mentioned production processes 1-10 as a solvent, according to the nature thereof.
In the above-mentioned Production Processes 1-10, it is also possible to use the compounds of general formulas [2], [2a], [3], [3a], [4], [4a], [5], [6], [6a], [7], [7a], [8], [9], [10], [11], [12] and [39] in the form of a salt, if desired. As said salt, the same salts as mentioned in the paragraph of salts of compound [1] can be used.
In case where the compounds of general formulas [2], [2a], [3], [3a], [4], [4a], [5], [6], [6a], [7], [7a], [8], [9], [10], [11], [12] and [39] have an isomer such as optical isomer, geometrical isomer, tautomer and the like, all these isomers are usable in the present invention. Further, all the hydrated products and solvated products and all the crystal forms can also be used in the present invention.
In cases where the compounds of general formulas [1], [1a], [2], [2a], [3], [3a], [4], [4a], [5], [6], [6a], [7], [7a], [8], [9], [10], [11], [12] and [39] have a hydroxyl group, an amino group or a carboxyl group, those hydroxyl, amino and carboxyl groups can be protected previously with a conventional protecting group. Such a protecting group can be eliminated after the reaction according to a method known per se, as occasion demands.
Further, it is possible to convert an N-alkoxyalkyl-N,N-dialkylamine derivative of general formula [1] and [1a] into the other N-alkoxyalkyl-N,N-dialkylamine derivative represented by general formula [1] or a salt thereof, by an appropriate combination of well known treatments such as oxidation, reduction, alkylation, halogenation, sulfonylation, substitution, dehydration, hydrolysis, etc.
The N-alkoxyalkyl-N,N-dialkylamine derivative of general formula [1] or a salt thereof thus obtained can be isolated and purified by conventional methods such as extraction, crystallization, distillation, column chromatography, etc.
Next, the processes for producing the compounds of general formula [2a], [4a], [7a], [2], [4], [7], [8] and [12] which are starting materials for production of the compounds of the present invention will be explained.
The compound of general formula [2a] can be produced according to methods known per se or an appropriate combination thereof. For example, compound [2a] can be produced by the following Production Process A.
Production Process A 
wherein R1, R2 and m are as defined above; R1a represents the same group as R1 except alkenyl group; R2a represents the same group as R2 except alkenyl group; R12 represents hydrogen atom, hydroxyl group or lower alkoxy group; and X5 represents a removing group.
As the removing group, for example, halogen atom, lower alkylsulfonyloxy group, arylsulfonyloxy group and the like can be referred to.
(A-1) A compound of general formula [13] is subjected to a conventional carbon chain-extending reaction, whereby a compound of general formula [14a] can be obtained.
This reaction can be carried out according to the method described in, for example, Jikken Kagaku Koza, Vol. 22, edited by Chemical Society of Japan, Pages 54-68 (1992, Maruzen) or any analogous method. As specific examples of the carbon chain-extending reaction, Wittig reaction, Wittig-Horner reaction and the like can be referred to.
(A-2) A compound of general formula [14a] is subjected to a conventional reduction reaction, whereby a compound of general formula [2a] can be obtained.
This reduction can be carried out according to the method described in, for example, Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 29-244 (1977, Maruzen) or any analogous method.
(A-3) A compound of general formula [14a] is subjected to a conventional catalytic hydrogenation, whereby a compound of general formula [15a] can be obtained.
This hydrogenation can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 333-448 (1977, Maruzen), or any analogous method.
(A-4) As an alternative process for producing a compound of general formula [15a], a process of subjecting a compound of general formula [13] to a conventional carbon chain-extending reaction can also be referred to.
This reaction can be carried out according to a method known per se, such as the method described in Jikken Kagaku Koza, Vol. 21, edited by Chemical Society of Japan, Pages 124-133 (1992, Maruzen), or any analogous method. As a concrete example of the carbon chain-lengthening reaction, Wittig reaction and the like can be referred to.
(A-5) A compound of general formula [16a] is subjected to a conventional cyanidation reaction, whereby a compound of general formula [17a] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [III], edited by Chemical Society of Japan, Pages 1428-1484 (1977, Maruzen), or any analogous method.
(A-6) A compound of general formula [17a] is subjected to a conventional hydrolysis, a conventional ester-forming alcoholysis or a conventional reduction reaction using a metal hydride such as diisobutyl aluminum hydride or the like, whereby a compound of general formula [15a] can be obtained.
These reactions can be carried out according to methods known per se, such as those described in Jikken Kagaku Koza, Vol. 22, edited by Chemical Society of Japan, Pages 1-83 (1992, Maruzen) and Jikken Kagaku Koza, Vol. 21, edited by Chemical Society of Japan, Pages 72-97 (1992, Maruzen), or any analogous methods.
(A-7) A compound of general formula [15a] is subjected to a conventional reduction reaction, whereby a compound of general formula [2a] can be obtained.
This reduction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 29-244 (1977, Maruzen) or any analogous method.
Further, a compound of general formula [2a] having a longer carbon chain can be produced by using a compound of general formula [15a] in which R12 is a hydrogen atom as a starting material, and repeating the reactions of (A-1), (A-3) and (A-4).
The compounds of general formulas [4a] and [7a] can be produced according to methods known per se or an appropriate combination of such methods, such as the Production Process B shown below:
Production Process B 
wherein R1, R2, X2, m and n are as defined above; R13 represents a lower alkoxy, dialkylamino or cyclic amino group; and X6 and X7 independently represent a halogen atom.
The term xe2x80x9ccyclic amino groupxe2x80x9d means a 5-, 6- or 7-membered ring cyclic amino group which contains one nitrogen atom as a hetero-atom constituting the ring and may additionally contain one or more oxygen atom or sulfur atom, such as pyrrolidinyl, piperidinyl, morpholyl, thiomorpholyl and the like.
(B-1) A compound of general formula [2a] is reacted with a compound of general formula [18a], whereby a compound of general formula [7a] can be obtained.
This reaction can be carried out according to a method known per se, such as the same process as in Production Process 1.
(B-2) A compound of general formula [2a] is reacted with a compound of general formula [19a] in the presence of a base, whereby a compound of general formula [20a] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [I], edited by Chemical Society of Japan, Pages 567-611 (1977, Maruzen), or any analogous method.
The base includes, for example, organic and inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydride, metallic sodium, lithium diisopropylamide, n-butyllithium, potassium tert-butoxide and the like.
The solvents which can be used in this reaction include, for example, water; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitrites such as acetonitrile and the like; tertiary alcohols such as tert-butanol and the like; hetero-aromatic compounds such as pyridine and the like; etc. These solvents can be used in the form of a mixture, if desired.
The compound of general formula [19a] and the base are used each in an equimolar amount to the compound of general formula [2a], and preferably in an amount of 1-20 mol per mol of compound [2a].
This reaction is usually carried out at a temperature of xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably at 0xc2x0 C. to +150xc2x0 C., for a period of 10 minutes to 20 hours.
(B-3) A compound of general formula [20a] is subjected to conventional hydrolysis of ester or amide, whereby a compound of general formula [4a] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in xe2x80x9cProtective Groups in Organic Synthesesxe2x80x9d (Theodra W. Green, 1981, John Wiley and Sons, Inc.) or any analogous method.
(B-4) A compound of general formula [4a] or a compound of general formula [20a] is subjected to conventional reduction reaction, whereby a compound of general formula [21a] can be obtained.
This reduction is carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, Pages 26-244 (1977, Maruzen) or any analogous method.
(B-5) A compound of general formula [21a] is treated with a halogenating agent or a sulfonylating agent in the presence or absence of a base, whereby a compound of general formula [7a] can be obtained.
The solvents which can be used in this reaction include, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; nitriles such as acetonitrile and the like; etc. These solvents can be used in the form of a mixture, if desired.
The bases which may be used as occasion demands, for example, organic and inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride and the like.
As the halogenating agent, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and the like can be referred to.
As the sulfonylating agent, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be referred to.
The halogenating agent and sulfonylating agent are both used at least in an equimolar amount to the compound of general formula [21a], and preferably in an amount of 1-2 mol per mol of compound [21a].
This reaction is carried out usually at a temperature of xe2x88x9250xc2x0 C. to +200xc2x0 C. and preferably at 0xc2x0 C. to +50xc2x0 C., for a period of 1-10 minutes to 30 hours.
In the above-mentioned Production Processes A and B, the compounds of general formulas [13], [14a], [15a], [16a], [17a], [2a], [4a], [19a], [20a] and [21a] can be used in the form of a salt, too, if desired. As the salt, the same salts as mentioned in the paragraph of the compound of general formula [1] can be referred to.
In the above-mentioned Production Processes A and B, the compounds of general formulas [13], [14a], [15a], [16a], [17a], [2a], [4a], [19a], [20a] and [21a] may have isomers such as optical isomer, geometrical isomer, tautomer, etc. In such a case, all these isomers can be used in the present invention. Further, hydrated products and solvated products thereof and all the crystal forms thereof can also be used in the invention.
Further, some of the compounds [13], [14a], [15a], [16a], [17a], [2a], [4a], [19a], [20a] and [21a] may have a hydroxyl group, an amino group or a carboxyl group. In such a case, it is possible to protect these groups with conventional protecting groups previously and to remove the protecting groups after the reaction according to a method known per se.
The compound of general formula [2] can be produced according to a method known per se or an appropriate combination of such methods. For example, it can be produced according to the following Production Process C.
Production Process C 
wherein R1, R2, R5, R6, R12, m and X5 are as defined above; R14 represents a lower alkoxy group; R15 represents a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group; R16 represents a cyano group or a lower alkoxycarbonyl group; and R17 represents a hydrogen atom, a cyano group, a carboxyl group or a lower alkoxycarbonyl group.
(C-1) A compound of general formula [13] is subjected to a conventional epoxidation reaction, whereby a compound of general formula [22] can be obtained.
This epoxidation reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [I], edited by Chemical Society of Japan, Pages 593-607 (1977, Maruzen), or any analogous method.
(C-2) A compound of general formula [22] is subjected to a conventional reduction reaction, whereby a compound of general formula [2] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 227-228 (1977, Maruzen), or any analogous method.
(C-3) A compound of general formula [23] is subjected to conventional carbon chain-extending reaction, whereby a compound of general formula [15a] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [II], edited by Chemical Society of Japan, Pages 1031-1032 (1977, Maruzen), or any analogous method. As a specific example of the carbon chain-extending reaction, Arndt-Eistert reaction or the like can be referred to.
(C-4) A compound of general formula [15b] is subjected to a conventional reduction reaction or addition of organo-metallic compound, whereby a compound of general formula [2] can be produced.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [I], edited by Chemical Society of Japan, Pages 474-477 and 512-520 (1977, Maruzen), or any analogous method.
(C-5) A compound of general formula [15a] can be converted to a compound of general formula [15] by subjecting compound [15a] to a conventional alkylation reaction.
This alkylation reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [II], edited by Chemical Society of Japan, Pages 637-1062 (1977, Maruzen), or any analogous method.
(C-6) As an alternative process thereof, a process of reacting a compound [16] with a compound of general formula [24] can be referred to. By this process, a compound of general formula [15] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [II], edited by Chemical Society of Japan, Pages 637-1062 (1977, Maruzen), or any analogous method.
It is possible, in this reaction, to carry out a hydrolysis and a decarboxylation reaction after completion of the reaction by a method known per se, as occasion demands.
(C-7) A compound of general formula [16] is subjected to a conventional cyanidation reaction, whereby a compound of general formula [17] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as (A-5).
(C-8) As an alternative process thereof, a process of subjecting a compound of general formula [17a] to a conventional alkylation reaction can be referred to. By this process, the compound [17a] can be converted to a compound of general formula [17].
This alkylation reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [III], edited by Chemical Society of Japan, Pages 1447-1448 (1977, Maruzen), or any analogous method.
(C-9) A compound of general formula [17] is subjected to a conventional hydrolysis, an ester-forming alcoholysis or a reduction using a metal hydride such as diisobutyl aluminum hydride or the like, whereby a compound of general formula [15] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as (A-6).
(C-10) A compound of general formula [15] wherein R12 is a hydrogen atom is subjected to a conventional epoxidation reaction, whereby a compound of general formula [25] can be produced.
This reaction can be carried out according to a method known per se, such as the same method as (C-1).
(C-11) A compound of general formula [25] is subjected to a conventional reduction or a ring-opening reaction using an organometallic compound, whereby a compound of general formula [2] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [I], edited by Chemical Society of Japan, Pages 478-481 and 524-529 (1977, Maruzen), or any analogous method.
(C-12) A compound of general formula [15] is subjected to a conventional reduction reaction or addition of organometallic compound, whereby a compound of general formula [2] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as (C-4).
(C-13) A compound of general formula [15] wherein R12 is a hydroxyl group or a lower alkoxy group can be converted to a compound of general formula [27] through a condensation reaction with a compound of general formula [26]. In case where R12 is a hydroxyl group, the compound [15] is converted to a reactive derivative thereof prior to the condensation reaction.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 767-775 (1977, Maruzen), or any analogous method.
(C-14) A compound of general formula [17] is subjected to a condensation reaction with a compound of general formula [26], whereby a compound of general formula [27] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 808-811 (1977, Maruzen), or any analogous method.
(C-15) A compound of general formula [27] is subjected to a conventional hydrolysis followed by a decarboxylation reaction, whereby a compound of general formula [28] can be obtained.
This reaction is carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 808-811 (1977, Maruzen), or any analogous method.
(C-16) As an alternative process thereof, a process of subjecting a compound of general formula [15] wherein R12 is a hydroxyl group or a lower alkoxy group to a conventional reduction reaction or an addition of organometallic compound can be referred to. By this process, a compound of general formula [28] can be obtained.
This reaction is carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 656-662 and 775-792 (1977, Maruzen), or any analogous method.
(C-17) A compound of general formula [17] is subjected to a conventional reduction reaction or an addition of organometallic compound, whereby a compound of general formula [28] can be obtained.
This reaction is carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 15, [II], edited by Chemical Society of Japan, Pages 652-656 and 808-810 (1977, Maruzen), or any analogous method.
(C-18) A compound of general formula [28] is subjected to a conventional reduction reaction or an addition of organometallic compound, whereby a compound of general formula [2] can be obtained.
This reaction is carried out according to a method known per se, such as the same method as (C-4).
The compounds of general formulas [4] and [7] can be produced according to methods known per se or an appropriate combination thereof. For examples, these compounds can be produced by Production Process D mentioned below.
Production Process D 
wherein R1, R2, R5, R6, R7, R8, R13, R15, R16, R17, X2, X6, X7, m and n are as defined above; R18 represents a protecting group for hydroxyl group which is unreactive under an alkaline condition; and X8 represents a halogen atom.
Examples of the protecting group which is not unreactive under basic condition include lower alkyl groups such as tert-butyl and the like; lower alkenyl groups such as allyl and the like; aryl-lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; lower alkoxy-lower alkyl groups such as methoxymethyl, 2-(trimethylsilyl))ethoxymethyl, 2-methoxy-1-methoxyethyl and the like; substituted silyl groups such as tert-butyldimethylsilyl, diphenylmethylsilyl and the like.
(D-1) A compound of general formula [2] is reacted with a compound of general formula [18], whereby a compound of general formula [7] can be obtained.
This reaction is carried out according to a method known per se, such as the same method as Production Process 1.
(D-2) A compound of general formula [2] is reacted with a compound of general formula [29] and the protecting group is removed, whereby a compound of general formula [21] can be obtained.
This reaction is achieved by carrying out the reaction according to a method known per se, such as the method as in Production Process 1, and then removing the protecting group.
(D-3) A compound of general formula [2] is reacted with a compound of general formula [19] in the presence of a base, whereby a compound of general formula [20] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as Production Process 5 (1).
(D-4) A compound of general formula [20] is subjected to a conventional hydrolysis of ether or amide, whereby a compound of general formula [4] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as (B-3).
(D-5) A compound of general formula [4] or general formula [20] is subjected to a conventional reduction reaction or addition of organometallic compound, whereby a compound of general formula [21] or a compound of general formula [30] can be obtained.
This reduction reaction or addition of organometallic compound can be carried out according to methods known per se, such as the same method as (C-12) or (C-16).
(D-6) A compound of general formula [4] is converted to a reactive derivative and then subjected to a condensation reaction with a compound of general formula [26], whereby a compound of general formula [31] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as (C-13)
(D-7) A compound of general formula [31] is subjected to a conventional hydrolysis and then to a decarboxylation reaction, whereby a compound of general formula [30] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as (C-15).
(D-8) A compound of general formula [30] is subjected to a conventional reduction reaction or an addition of organometallic compound, whereby a compound of general formula [21] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as (C-4).
(D-9) A compound of general formula [21] is treated with a halogenating agent or a sulfonylating agent in the presence or absence of a base, whereby a compound of general formula [7] can be obtained.
This reaction can be carried out according to a well known method, such as the same method as (B-5).
The compound of general formula [8] can be produced according to methods well known in themselves or an appropriate combination thereof, such as the Production Process E shown below.
Production Process E 
wherein R1, R2, R3, R5, R6, R7, R8, X2, m and n are as defined above.
(E-1) A compound of general formula [4] or reactive derivative thereof is reacted with a compound of general formula [32], whereby a compound of general formula [33] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as Production Process 2 (1).
(E-2) A compound of general formula [33] is subjected to a conventional reduction reaction, whereby a compound of general formula [8] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as Production Process 2 (2).
(E-3) A compound of general formula [7] is reacted with a compound of general formula [32] in the presence or absence of a base, whereby a compound of general formula [8] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as Production Process 3.
The compound of general formula [12] can be produced according to methods known per se, or an appropriate combination thereof, such as the production Process F shown below.
Production Process F 
wherein R2, R3, R4, R5, R6, R7, R8, R10, R11, X1, X3, m and n are as defined above.
(F-1) A compound of general formula [34  is reacted with a compound of general formula [39] in the presence of a base, whereby a compound of general formula [35] can be produced.
This reaction can be carried out according to a method known per se, such as the same method as Production Process 5.
(F-2) A compound of general formula [35] is subjected to a conventional reduction reaction, whereby a compound of general formula [12] can be obtained.
This reaction can be carried out according to a method known per se, such as the same method as Production Process 2 (2).
(F-3) A compound of general formula [34] is reacted with a compound of general formula [3] in the presence of a base, whereby a compound of general formula [12] can be obtained.
This reaction is carried out according to a method known per se, such as the same method as Production Process 1.
Alternatively, it is also possible to produce a compound of general formula [12] by a method other than the above, namely by using a compound of general formula [34] as a starting material and referring to the processes for producing the compound of general formula [1] and starting material thereof.
Next, the compounds of general formulas [13] and [23] which are starting materials for production of the starting intermediate compounds can be produced according to methods known per se or an appropriate combination thereof, such as the processes mentioned below.
Production Process G 
wherein R1, R2, R10, R11 and D are as defined above; R19 represents a hydrogen atom or a protecting group for carboxyl group; and X9 represents a halogen atom.
(G-1) A compound of general formula [36] is subjected to a conventional ring-closing reaction, whereby a compound of general formula [37] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in xe2x80x9cChemistry of Heterocyclic Compoundsxe2x80x9d, Pages 16-80 (1988, Kodansha) and Shin Jikken Kagaku Koza, Vol. 14, [IV], edited by Chemical Society of Japan, Pages 1879-2406 (1977, Maruzen), or any analogous method.
(G-2) A compound of general formula [37] is subjected to a conventional oxidation reaction, whereby a compound of general formula [13] or [37] can be obtained.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [II], edited by Chemical Society of Japan, Pages 636-643 and 922-926 (1977, Maruzen), or any analogous method.
(G-3) As an alternative process, a process of subjecting a compound of general formula [37] to a conventional halogenation reaction to form a compound of general formula [16b] and then subjecting the compound [16b] to an oxidation reaction to form a compound of general formula [13] can be referred to.
This reaction can be carried out according to a method known per se, such as the method described in Shin Jikken Kagaku Koza, Vol. 14, [I], edited by Chemical Society of Japan, Pages 331-344 (1977, Maruzen) and Shin Jikken Kagaku Koza, Vol. 14, [II], edited by Chemical Society of Japan, Pages 636-643 (1977, Maruzen), or any analogous method.
(G-4) A compound of general formula [38] is subjected to a conventional ring-closing reaction, whereby a compound of general formula [23] can be produced.
This reaction can be carried out according to a method known per se, such as the method described in xe2x80x9cChemistry of Heterocyclic Compoundsxe2x80x9d, Pages 16-80 (1988, Kodansha) and Shin Jikken Kagaku Koza, Vol. 14, [IV], edited by Chemical Society of Japan, Pages 1879-2406 (1977, Maruzen), or any analogous method.
The ring-closing method of Production Process G can be applied to the production of the compounds of general formulas [2], [2a], [15], [15a], [15b], [20], [20a], [21] and [21a].
In the above-mentioned Production Processes C, D, E, F and G, the compounds of general formulas [2], [3], [4], [7], [8], [12], [13], [15], [15a], [15b], [16], [16b], [17], [17a], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38] and [39] can be used in the form of a salt, too, if desired. As said salt, the same salts as mentioned in the paragraph of the compounds of general formula [1] can be referred to.
In cases where the compounds of general formulas [2], [3], [4], [7], [8], [12], [13], [15], [15a], [15b], [16], [16b], [17], [17a], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38] and [39] have an isomer such as optical isomer, geometrical isomer, tautomer or the like, all these isomers can be used in the present invention. Further, hydrated products and solvated products and all the crystal form thereof are also usable.
Some of the compounds of the general formulas [2], [3], [4], [7], [8], [12], [13], [15], [15a], [15b], [16], [16b], [17], [17a], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38] and [39] may have a hydroxyl group, an amino group or a carboxyl group. In such cases, it is possible to protect these hydroxyl, amino or carboxyl group previously and to remove these protecting groups after the reaction according to a method known per se, as occasion demands.
The compound of the present invention can be made into a pharmaceutical preparation such as oral agent (tablet, capsule, powder, granule, fine granule, pill, suspension, emulsion, solution, syrup and the like), injection, suppository, external preparation (ointment, plaster, etc.), aerosol, etc. by compounding the compound of the invention with various pharmaceutical additives such as excipient, binder, disintegrator, disintegration controller, solidification-adhesion preventor, lubricant, absorption-adsorption carrier, solvent, filler, isotonizing agent, dissolution aid, emulsifier, suspending agent, thickener, coating agent, absorption promoter, gelation-coagulation promoter, light stabilizer, preservative, moisture-proofing agent, emulsion-suspension-dispersion stabilizer, color protecting agent, de-oxygenating antioxidant, flavoring agent, colorant, forming agent, antifoaming agent, soothing agent, antistatic agent, buffering pH regulator and the like.
The agents mentioned above can be made into preparations by the conventional methods. The oral solid preparations such as tablet, powder, granule, etc. can be produced in the conventional manner by the use of pharmaceutical additives for solid preparations, of which the examples include an excipient such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolinite, crystalline cellulose, anhydrous calcium secondary phosphate, partially pregelatinized starch, corn starch, alginic acid and the like; a binder such as single syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, sodium alginate, gum arabic, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, water, ethanol and the like; a disintegrator such as dry starch, alginic acid, agar powder, starch, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium starch glycolate and the like; a disintegration-controller such as stearyl alcohol, stearic acid, cacao butter, hydrogenated oils and the like; a solidification-adhesion preventor such as aluminum silicate, calcium hydrogen phosphate, magnesium oxide, talc, silicic acid anhydride and the like; a lubricant such as Carnauba wax, light silicic acid, aluminum silicate, magnesium silicate, hardened oils, hardened vegetable oil derivatives, sesame oil, whitened bees wax, titanium oxide, dried aluminum oxide gel, stearic acid, calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate, sodium lauryl sulfate, polyethylene glycol and the like; an absorption promoter such as quaternary ammonium salts, sodium lauryl sulfate, urea, enzyme and the like; an absorption-adsorption carrier such as starch, lactose, kaolinite, bentonite, silicic acid anhydride, hydrated silicon dioxide, magnesium metasilicate-aluminate, colloidal silicic acid and the like; etc.
Further, the tablets can be made into tablets coated with usual skins as occasion demands, of which the examples include sugar-coated tablet, gelatin-coated tablet, tablet with intragastrically soluble coating, tablet with intraintestinally soluble coating, tablet with water soluble film coating, etc.
Capsules can be produced by mixing the main ingredient with the above-mentioned pharmaceutical additives and filling the mixture into a hard gelatin capsule, soft capsule, or the like.
Further, it is also possible to form the compound of the present invention into an aqueous or oily suspension, solution, syrup or elixir by mixing it with the above-mentioned various liquid preparation-forming additives and treating the mixture in a conventional manner.
Suppositories can be produced by adding an appropriate absorption promoter to polyethylene glycol, cacao butter, lanolin, higher alcohol, higher alcohol ester, gelatin, semi-synthetic glyceride, Witepsol or the like and forming the mixture into a preparation.
Injections can be produced in the conventional manner by the use of pharmaceutical additives for forming liquid preparations, of which the examples include a diluent such as water, ethyl alcohol, Macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid, sodium hydroxide and the like; a pH regulator and a buffering agent such as sodium citrate, sodium acetate, sodium phosphate and the like; a stabilizer such as sodium pyrophosphate, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid and the like; an isotonizing agent such as sodium chloride, glucose, mannitol, glycerin and the like; a dissolution aid such as sodium carboxymethyl cellulose, propylene glycol, sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerin and the like; a pain stopping agent such as calcium gluconate, chlorobutanol, glucose, benzyl alcohol and the like; a local anesthetic; etc.
Ointments in the forms of paste, cream and gel can be produced by mixing the compound of the present invention with pharmaceutical additives including a base such as white Vaseline, polyethylene, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicone, bentonite and the like; a preservative such as methyl p-oxybenzoate, ethyl p-oxybenzoate, propyl p-oxybenzoate and the like; a stabilizer; a wetting agent; etc. and forming the mixture into a preparation in the conventional manner.
For producing a plaster, a conventional support can be coated with the above-mentioned ointment, cream, gel, paste or the like in the usual manner. As the support, woven or unwoven fabrics made of cotton, staple fiber or chemical fiber, films of plasticized polyvinyl chloride, polyethylene, polyurethane or the like, or foamed sheets can be used.
Although the method for administering the above-mentioned pharmaceutical preparations is not particularly limited and is properly determined depending on the pharmaceutical form, the age, sex and other conditions of patient, and symptom of the patient.
Dosage of the active ingredient of the pharmaceutical preparation of the present invention should be properly decided in accordance with the method of use, the age and sex of patient, pathosis of patient, and other conditions. Usually, the active ingredient may be administered to an adult in dose of 0.1 to 500 mg per day in one portion or several portions.
Next, the pharmacological activities of the typical compounds of the present invention will be described.
[Anti-hypoxic Activity]
A test compound (100 mg/kg) dissolved in distilled water is orally administered to ddY male mice of 5-6 weeks age (6-10 heads per group). Thirty minutes after the administration, each mouse was introduced into a glass vessel, and a gas mixture consisting of 4% of oxygen and 96% of nitrogen was passed through the glass vessel at a rate of 5 L/minute. The period of the time from the beginning of sending the gas to the death of the animal was measured.
To the control group, only distilled water was orally given. Anti-hypoxic activity of test compound was calculated according to the following equation:
(Survival time of mouse in administered group)÷(Survival time of mouse in control group)xc3x97100(%)
As the result, the hypoxic activities were as follows:
the compound of Example 10: 170%,
the compound of Example 13: 160%,
the compound of Example 16: 158%,
the compound of Example 20: 155%,
the compound of Example 31: 248%,
the compound of Example 49: 173%,
the compound of Example 53: 200%,
the compound of Example 68: 202%,
the compound of Example 70: 213%,
the compound of Example 76: 194%,
the compound of Example 101: 187%,
the compound of Example 102: 210%,
the compound of Example 144: 250%,
the compound of Example 158: 179%.
[Nerve-regeneration Promoting Activity]
The test was carried out according to the description of Experimental Neurology, Vol. 140, Page 198 (1996).
SD rats (male, 6 weeks age, body weight 160-200 g) were anesthetized with Pentobarbital. The left sciatic nerve was exposed from the upper femoral muscular texture and peeled off from the surrounding texture, while taking care so as to give no injury to the muscular fiber.
By means of a needle holder with a flattened and smoothed contact surface, the sciatic nerve was pressed and crushed for a period of 90 seconds in a zone extending over about 10 mm from the branched part and having a width of 1.5 mm at the central portion. The crushed zone was marked with a thread at the end of neurilemma, and the operated portion was sutured. One hour after the crushing, a test compound dissolved in physiological salt solution was administered intra-abdominally at a dosage of 10 mg/kg. Thereafter, the same administration as above was repeated twice per day far 5 days.
Six days after the operation, the operated portion was again opened under an anesthesia using Pentobarbital to expose the sciatic nerve, and a forceps was made to contact to the nerve from a position about 25 mm distant from the crushed part. The forceps was slowly moved toward the crushed part until a reflex reaction appeared. The distance between the portion exhibiting reflex and the crushed portion was measured, and regarded as a regeneration distance. To the control group, only a saline was given.
The sciatic nerve regeneration rate of the test compound was calculated according to the following equation:
(Regeneration distance in administration group)÷(Regeneration distance in control group)xc3x97100(%)
As a result, the regeneration rates of sciatic nerve were as follows:
the compound of Example 10: 117%,
the compound of Example 16: 115%,
the compound of Example 27: 126%.
[An Activity of Inhibiting the Axcex2-induced Nerve Cell Death]
The effect of inhibiting the death of cultured nerve cell induced by Axcex2 was examined by a modification of the method described in Brain Research, Vol. 639, Page 240 (1994).
Cerebral cortex excised from the brain of an embryo of Wistar rat (embryonal age 17-19 days) was cut into small pieces and then treated with trypsin to dissociate the nerve cells. The cells were spread onto a 48-well tissue-culture plate at a rate of 1xc3x97105 cells per well, and cultured under a condition of 5% carbon dioxide, 37xc2x0 C., in a Dulbecco modified Eagle medium to which B27 additives (product of GIBCO BRL) and 3.6 mg/mL glucose were added.
When the cultured had been continued for 12-13 days, a solution of potassium chloride was added so as to give a final concentration of 25 mmol/L, immediately after which a test agent was added. Twenty four hours after addition of the test agent, Axcex2 (25-35 peptide residues) dissolved in distilled water was added so as to give a final concentration of 20 xcexcmol/L. Twenty four hours after addition of Axcex2, the medium was changed to a medium prepared by adding test compound to Dulbecco modified Eagle medium to which B27 and 3.6 mg/mL glucose were added.
The inhibitory activity of test agent on the cultured nerve cell death was expressed by using the activity of inhibiting the decrease of MTT reducing ability as an index. That is, 48 hours after changing the medium, MTT assay developed by Mossmann [Journal of Immunological Methods, Vol. 65, Page 55 (1983)] was carried out, and the inhibition rate (%) of the agent on the decrease of MTT assay value induced by Axcex2 was calculated.
xe2x80x83Inhibition rate=[(Axcex2+MTT assay value of agentxe2x88x92added group)xe2x88x92(MTT assay value of Axcex2xe2x88x92added group)]÷[MTT assay value of no addition groupxe2x88x92MTT assay value of Axcex2xe2x88x92added group]xc3x97100
As a result, at a concentration of 0.1 xcexcM, the inhibition rates were as follows:
the compound of Example 68: 28%,
the compound of Example 119: 39%,
the compound of Example 137: 37%.
[Activity of Inhibiting the HNE-induced Nerve Cell Death]
The protecting effect against the death of cultured nerve cells induced by HNE was examined by a modification of the method described in the Journal of Neuroscience, Vol. 17, Page 5089 (1997).
Cerebral cortex excised from the brain of an embryo of Wistar rat (embryonal age 17-19 days) was cut into small pieces and then treated with trypsin to dissociate the nerve cells. The cells were spread onto a 48-well tissue-culture plate at a rate of 5xc3x97105 cells per well, and cultured under a condition of 5% carbon dioxide, 37xc2x0 C., in a Dulbecco modified Eagle medium to which 10% fetal calf serum and 3.6 mg/mL glucose were added.
In order to inhibit the proliferation of glia cells, cytosine arabinoside was added so as to give a final concentration of 10 xcexcmol/L, from the day one after starting the culture. When the culture had been continued for 2 days, the medium was changed to a Dulbecco modified Eagle medium to which 10% fetal calf serum and 3.6 mg/mL glucose were added. When the culture had been continued for 7-8 days, a test agent was added, after which HNE was immediately added so as to give a final concentration of 25 xcexcmol/L.
The inhibitory activity of an agent on the cultured nerve cell death was decreased by using the inhibitory activity on the depression of MTT reducing ability as an index. That is, 24 hours after addition of a test agent, MTT assay [Journal of Immunological Methods, Vol. 65, Page 55 (1983)] developed by Mossmann was carried out, based on which inhibitory rate (%) of the agent on the decrease of MTT assay induced by HNE was calculated.
Inhibitory rate=[MTT assay value of (HNE+agent)xe2x88x92added group)xe2x88x92(MTT assay value of HNExe2x88x92added group)]÷(MTT assay value of no addition groupxe2x88x92MTT assay value of HNExe2x88x92added group)]xc3x97100
As a result, at a concentration of 0.1 xcexcM, the inhibitory rates were as follows:
the compound of Example 10: 58%,
the compound of Example 20: 69%,
the compound of Example 68: 57%,
the compound of Example 76: 49%,
the compound of Example 105: 31%.